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GLOBALSTRATEGY FORASTHMAMANAGEMENT AND PREVENTION

UPDATED 2009

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Global Strategy for Asthma Management and PreventionThe GINA reports are available on www.ginasthma.org.

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GINA EXECUTIVE COMMITTEE*

Eric D. Bateman, MD, ChairUniversity Cape Town Lung InstituteCape Town, South Africa

Louis-Philippe Boulet, MDHpital LavalSainte-Foy , Quebec, Canada

Alvaro A. Cruz, MDFederal University of BahiaSchool of MedicineSalvador, Brazil

Mark FitzGerald, MDUniversity of British ColumbiaVancouver, BC, Canada

Tari Haahtela, MDHelsinki University Central HospitalHelsinki, Finland

Mark L. Levy, MDUniversity of EdinburghLondon England, UK

Paul O'Byrne, MDMcMaster UniversityOntario, Canada

Ken Ohta, MD, PhDTeikyo University School of MedicineTokyo, Japan

Pierluigi Paggiaro, MDUniversity of PisaPisa, Italy

Soren Erik Pedersen, M.D.Kolding HospitalKolding, Denmark

Manuel Soto-Quiroz, MDHospital Nacional de NiosSan Jos, Costa Rica

Gary W. Wong, MDChinese University of Hong KongHong Kong ROC

GINA SCIENCE COMMITTEE*

Mark FitzGerald, MD, ChairUniversity of British ColumbiaVancouver, BC, Canada

Neil Barnes, MDLondon Chest HospitalLondon, England, UK

Peter J. Barnes, MDNational Heart and Lung InstituteLondon, England, UK

Eric D. Bateman, MDUniversity Cape Town Lung InstituteCape Town, South Africa

Allan Becker, MDUniversity of ManitobaWinnipeg, Manitoba, Canada

Jeffrey M. Drazen, MDHarvard Medical SchoolBoston, Massachusetts, USA

Robert F. Lemanske, Jr., M.D.University of WisconsinSchool of MedicineMadison, Wisconsin, USA

Paul O'Byrne, MDMcMaster UniversityOntario, Canada

Ken Ohta, MD, PhDTeikyo University School of MedicineTokyo, Japan

Soren Erik Pedersen, M.D.Kolding HospitalKolding, Denmark

Emilio Pizzichini, MDUniversidade Federal de Santa CatarinaFlorianpolis, SC, Brazil

Helen K. Reddel, MDWoolcock Institute of Medical ResearchCamperdown, NSW, Australia

Sean D. Sullivan, PhDProfessor of Pharmacy, Public HealthUniversity of WashingtonSeattle, Washington, USA

Sally E. Wenzel, M.D.University of PittsburghPittsburgh, Pennsylvania, USA

Heather J. Zar, MDUniversity of Cape TownCape Town, South Africa

Global Strategy for Asthma Management and Prevention 2009 (update)

*Disclosures for members of GINA Executive and Science Committees can be found at:http://www.ginasthma.com/Committees.asp?l1=7&l2=2

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Asthma is a serious global health problem. People of allages in countries throughout the world are affected by thischronic airway disorder that, when uncontrolled, can placesevere limits on daily life and is sometimes fatal. The

prevalence of asthma is increasing in most countries,especially among children. Asthma is a significant burden,not only in terms of health care costs but also of lostproductivity and reduced participation in family life.

During the past two decades, we have witnessed manyscientific advances that have improved our understandingof asthma and our ability to manage and control iteffectively. However, the diversity of national health careservice systems and variations in the availability of asthmatherapies require that recommendations for asthma carebe adapted to local conditions throughout the globalcommunity. In addition, public health officials require

information about the costs of asthma care, how toeffectively manage this chronic disorder, and educationmethods to develop asthma care services and programsresponsive to the particular needs and circumstanceswithin their countries.

In 1993, the National Heart, Lung, and Blood Institutecollaborated with the World Health Organization toconvene a workshop that led to a Workshop Report:Global Strategy for Asthma Management and Prevention.This presented a comprehensive plan to manage asthmawith the goal of reducing chronic disability and prematuredeaths while allowing patients with asthma to lead

productive and fulfilling lives.

At the same time, the Global Initiative for Asthma (GINA)was implemented to develop a network of individuals,organizations, and public health officials to disseminateinformation about the care of patients with asthma while atthe same time assuring a mechanism to incorporate theresults of scientific investigations into asthma care.Publications based on the GINA Report were preparedand have been translated into languages to promoteinternational collaboration and dissemination ofinformation. To disseminate information about asthmacare, a GINA Assembly was initiated, comprised of asthma

care experts from many countries to conduct workshopswith local doctors and national opinion leaders and to holdseminars at national and international meetings. Inaddition, GINA initiated an annual World Asthma Day (in2001) which has gained increasing attention each year toraise awareness about the burden of asthma, and toinitiate activities at the local/national level to educatefamilies and health care professionals about effectivemethods to manage and control asthma.

In spite of these dissemination efforts, international

surveys provide direct evidence for suboptimal asthmacontrol in many countries, despite the availability of

effective therapies. It is clear that if recommendations

contained within this report are to improve care of peoplewith asthma, every effort must be made to encouragehealth care leaders to assure availability of and access to

medications, and develop means to implement effectiveasthma management programs including the use ofappropriate tools to measure success.

In 2002, the GINA Report stated that it is reasonable to

expect that in most patients with asthma, control of thedisease can, and should be achieved and maintained.

To meet this challenge, in 2005, Executive Committeerecommended preparation of a new report not only to

incorporate updated scientific information but to implement

an approach to asthma management based on asthmacontrol, rather than asthma severity. Recommendations toassess, treat and maintain asthma control are provided inthis document. The methods used to prepare this

document are described in the Introduction.

It is a privilege for me to acknowledge the work of themany people who participated in this update project, as

well as to acknowledge the superlative work of all whohave contributed to the success of the GINA program.

The GINA program has been conducted through

unrestricted educational grants from AstraZeneca,

Boehringer Ingelheim, Chiesi Group, GlaxoSmithKline,Meda Pharma, Merck, Sharp & Dohme, Mitsubishi TanabePharma, Novartis, Nycomed, PharmAxis and Schering-

Plough. The generous contributions of these companiesassured that Committee members could meet together todiscuss issues and reach consensus in a constructive and

timely manner. The members of the GINA Committeesare, however, solely responsible for the statements and

conclusions presented in this publication.

GINA publications are available through the Internet(http://www.ginasthma.org).

Eric Bateman, MD

Chair, GINA Executive CommitteeUniversity of CapeTown Lung Institute

Cape Town, South Africa

PREFACE

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PREFACE .........................................................................ii

METHODOLOGY AND SUMMARY OF NEW

RECOMMENDATION, 2007 UPDATE.........................vi

INTRODUCTION ..............................................................x

CHAPTER 1. DEFINITION AND OVERVIEW..................1

KEY POINTS ....................................................................2

DEFINITION .....................................................................2

THE BURDEN OF ASTHMA.............................................3Prevalence, Morbidity and Mortality .............................3Social and Economic Burden .......................................3

FACTORS INFLUENCING THE DEVELOPMENT ANDEXPRESSION OF ASTHMA..........................................4

Host Factors................................................................4Genetic.....................................................................4Obesity.....................................................................5Sex...........................................................................5

Environmental Factors ................................................5Allergens..................................................................5Infections..................................................................5Occupational sensitizers...........................................5Tobacco smoke........................................................6Outdoor/Indoor air pollution......................................6Diet...........................................................................7

MECHANISMS OF ASTHMA............................................7Airway Inflammation In Asthma....................................7

Inflammatory cells....................................................7Inflammatory mediators............................................7Structural changes in the airways.............................8

Pathophysiology...........................................................8Airway hyperresponsiveness....................................8

Special Mechanisms ....................................................8Acute exacerbations.................................................8Nocturnal asthma.....................................................9Irreversible airflow limitation.....................................9Difficult-to-treat asthma............................................9

Smoking and asthma................................................9

REFERENCES .................................................................9

CHAPTER 2. DIAGNOSIS AND CLASSIFICATION.....15

KEY POINTS ..................................................................16INTRODUCTION ............................................................16

CLINICAL DIAGNOSIS...................................................16Medical History...........................................................16

Symptoms..............................................................16

Cough variant asthma............................................16Exercise-Induced bronchospasm...........................17Physical Examination .................................................17Tests for Diagnosis and Monitoring ............................17

Measurements of lung function...............................17Spirometry..............................................................18Peak expiratory flow...............................................18Measurement of airway responsiveness................19Non-Invasive markers of airway inflammation........19Measurements of allergic status.............................19

DIAGNOSTIC CHALLENGES ANDDIFFERENTIAL DIAGNOSIS.......................................20

Children 5 Years and Younger ...................................20Older Children and Adults ..........................................20The Elderly.................................................................21Occupational Asthma .................................................21Distinguishing Asthma from COPD ............................21

CLASSIFICATION OF ASTHMA.....................................22Etiology ......................................................................22Phenotype..................................................................22Asthma Control ..........................................................22Asthma Severity.........................................................23

REFERENCES...............................................................23

CHAPTER 3. ASTHMA MEDICATIONS ........................27

KEY POINTS ..................................................................28

INTRODUCTION ............................................................28

ASTHMA MEDICATIONS: ADULTS...............................28Route of Administration..............................................28Controller Medications................................................29

Inhaled glucocorticosteroids...................................29Leukotriene modifiers.............................................30Long-acting inhaled2-agonists.............................30

Theophylline...........................................................31Cromones: sodium cromoglycate and

nedocromil sodium........................................31Long-acting oral2-agonists...................................32Anti-IgE..................................................................32Systemic glucocorticosteroids................................32Oral anti-allergic compounds..................................32Other controller therapies.......................................32Allergen-specific immunotherapy............................33

GLOBAL STRATEGY FOR ASTHMA MANAGEMENT AND PREVENTIONTABLE OF CONTENTS

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Reliever Medications...................................................34Rapid-acting inhaled2-agonists............................34Systemic glucocorticosteroids................................34Anticholinergics......................................................34Theophylline...........................................................35Short-acting oral2-agonists..................................35

Complementary and Alternative Medicine...................35

ASTHMA TREATMENT: CHILDREN.............................35Route of Administration..............................................35Controller Medications................................................36

Inhaled glucocorticosteroids...................................36Leukotriene modifiers.............................................38Long-acting inhaled2-agonists.............................38Theophylline...........................................................39Cromones: sodium cromoglycate and nedocromil

sodium .........................................................39Long-acting oral2-agonists...................................39Systemic glucocorticosteroids................................39

Reliever Medications...................................................40

Rapid-acting inhaled2-agonists and short-actingoral2-agonists..............................................40

Anticholinergics......................................................40

REFERENCES ...............................................................40

CHAPTER 4. ASTHMA MANAGEMENT ANDPREVENTION ................................................................49

INTRODUCTION ............................................................50

COMPONENT 1: DEVELOP PATIENT/DOCTOR PARTNERSHIP...........................................50

KEY POINTS ..................................................................50

INTRODUCTION ............................................................50

ASTHMA EDUCATION...................................................51At the Initial Consultation...........................................52

Personal Asthma Action Plans ..................................52Follow-up and Review ...............................................52Improving Adherence................................................52

Self-Management in Children....................................52

THE EDUCATION OF OTHERS.....................................53

COMPONENT 2: IDENTIFY AND REDUCE EXPOSURETO RISK FACTORS ....................................................54

KEY POINTS ..................................................................54

INTRODUCTION ............................................................54

ASTHMA PREVENTION.................................................54

PREVENTION OF ASTHMA SYMPTOMS ANDEXACERBATIONS....................................................55

Indoor Allergens .......................................................55Domestic mites.......................................................55

Furred animals.......................................................55Cockroaches..........................................................55Fungi......................................................................56

Outdoor Allergens ......................................................56

Indoor Air Pollutants ..................................................56Outdoor Air Pollutants ................................................56Occupational Exposures ............................................56

Food and Food Additives ...........................................56Drugs .........................................................................57

Influenza Vaccination .................................................57Obesity.......................................................................57

Emotional Stress ........................................................57Other Factors That May Exacerbate Asthma .............57

COMPONENT 3: ASSESS, TREAT AND MONITORASTHMA......................................................................57

KEY POINTS ..................................................................57

INTRODUCTION ............................................................57

ASSESSING ASTHMA CONTROL.................................58

TREATING TO ACHIEVE CONTROL.............................58Treatment Steps for Achieving Control........................58

Step 1: As-needed reliever medication..................58Step 2: Reliever medication plus a singlecontroller.........................................................60

Step 3: Reliever medication plus one or twocontrollers.......................................................60

Step 4: Reliever medication plus two or morecontrollers.......................................................61

Step 5: Reliever medication plus additionalcontroller options............................................61

MONITORING TO MAINTAIN CONTROL ......................61

Duration and Adjustments to Treatment ......................61

Stepping Down Treatment When Asthma Is

Controlled.................................................................62Stepping Up Treatment In Response To Loss Of

Control .....................................................................62

Difficult-to-Treat-Asthma .............................................63

COMPONENT 4 - MANAGE ASTHMAEXACERBATIONS......................................................64

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KEY POINTS ..................................................................64

INTRODUCTION ............................................................64

ASSESSMENT OF SEVERITY.......................................65

MANAGEMENTCOMMUNITY SETTINGS ...................65Treatment...................................................................66

Bronchodilators......................................................66Glucocorticosteroids...............................................66

MANAGEMENTACUTE CARE SETTINGS ..................66

Assessment ................................................................66

Treatment....................................................................68Oxygen...................................................................68Rapid-acting inhaled2agonists...........................68Epinephrine............................................................68

Additional bronchodilators...........................................68Systemic glucocorticosteroids................................68Inhaled glucocorticosteroids...................................69Magnesium.............................................................69Helium oxygen therapy...........................................69Leukotriene modifiers.............................................69Sedatives...............................................................69

Criteria for Discharge from the Emergency

Department vs. Hospitalization.................................69

COMPONENT 5. SPECIAL CONSIDERATIONS..........70Pregnancy.....................................................................70

Surgery .........................................................................70

Rhinitis, Sinusitis, And Nasal Polyps .............................71

Rhinitis...................................................................71Sinusitis..................................................................71Nasal polyps...........................................................71

Occupational Asthma....................................................71

Respiratory Infections ...................................................72

Gastroesophageal Reflux..............................................72

Aspirin-Induced Asthma................................................72

Anaphylaxis and Asthma...............................................73

REFERENCES ...............................................................73

CHAPTER 5. IMPLEMENTATION OF ASTHMAGUIDELINES IN HEALTH SYSTEMS .........................87

KEY POINTS ..................................................................88

INTRODUCTION ............................................................88

GUIDELINE IMPLEMENTATION STRATEGIES............88

ECONOMIC VALUE OF INTERVENTIONS ANDGUIDELINE IMPLEMENTATION IN ASTHMA...........89

Utilization and Cost of Health Care Resources.........89Determining the Economic Value of Interventions in

Asthma ...................................................................90

GINA DISSEMINATION/IMPLEMENTATION

RESOURCES ............................................................90

REFERENCES...............................................................91

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When the Global Initiative for Asthma (GINA) program wasinitiated in 1993, the primary goal was to producerecommendations for asthma management based on thebest scientific information available. Its first report,NHLBI/WHO Workshop Report: Global Strategy forAsthma Management and Preventionwas issued in 1995and revised in 2002 and 2006. These reports, and theircompanion documents, have been widely distributed andtranslated into many languages. The 2006 report wasbased on research published through June, 2006 and canbe found on the GINA website (www.ginasthma.org).

The GINA Science Committee was established in 2002 toreview published research on asthma management andprevention, to evaluate the impact of this research onrecommendations in the GINA documents related tomanagement and prevention, and to post yearly updateson the GINA website. The first update of the 2006 report(2007 update) included the impact of publications fromJuly 1, 2006 through June 30, 2007; the 2008 updatedincluded the impact of publications from July 1, 2007through June 30, 2008. This 2009 update includes theimpact of publications from July 1, 2008 through June 30,2009.

Methods: The methodology used to produce this 2009update included a Pub Med search using search fieldsestablished by the Committee: 1) asthma, All Fields, Allages, only items with abstracts, Clinical Trial, Human,sorted by Authors;and 2) asthma AND systematic, Allfields, ALL ages, only items with abstracts, Human, sortedby author. In addition, publications in peer review journalsnot captured by Pub Med could be submitted to individualmembers of the Committee providing an abstract and thefull paper were submitted in (or translated into) English.

All members of the Committee received a summary ofcitations and all abstracts. Each abstract was assigned to

at least two Committee members, although all memberswere offered the opportunity to provide an opinion on anyabstract. Members evaluated the abstract or, up to her/hisjudgment, the full publication, by answering specific writtenquestions from a short questionnaire, and to indicate if thescientific data presented impacted on recommendations inthe GINA report. If so, the member was asked tospecifically identify modifications that should be made. Theentire GINA Science Committee met twice yearly to

discuss each publication that was felt would have animpact on asthma management and prevention by at least1 member of the Committee, and to reach a consensus onthe changes in the report. In the absence of consensusdisagreements were decided by an open vote of the fullcommittee.

Summary of Recommendations in the 2009 Update:Between July 1, 2008 and June 30, 2009, 392 articles metthe search criteria; 10 additional publications were broughtto the attention of the committee. Of the 402 articles, 23papers were identified as having an impact on the GINAReport (updated 2009) that was posted on the website inDecember 2009 either by: 1) confirming, that is, adding toor replacing an existing reference, or 2) modifying, that is,changing the text or introducing a concept requiring a newrecommendation to the report. The summary is reportedin three segments: A) Modifications in the text; B)References that provided confirmation or an update ofprevious recommendations; and C) Changes ormodifications to the text.

Asthma in Children 5 Years and Younger: In 2008, anumber of pediatric experts developed a report whichfocused on asthma care in children 5 years and younger.

The Global Strategy for Asthma Management andPrevention in Children 5 Years and Younger was releasedin early 2009 (can be found on www.ginasthma.org).Accordingly, the Executive Summary Managing Asthma inChildren 5 Years and Younger that appeared on pagesxiv xvii is deleted see section C.

Asthma Control: In review of the published literature, theCommittee determined that many changes were requiredin the segment Classification of Asthma. Accordingly, anew segment appears beginning on page 22 see sectionD.1).

Evidence Reviews: In the preparation of GINA reports,including this 2009 update, levels of evidence has beencompleted using four categories as described on page xiii.The committee has had extensive discussions internally,as well as with proponents of a new methodology fordescribing recommendations (the GRADE system). Theimplications for the widespread adaptation of this systemhas been explored by the Committee with regard toresource implications, especially given the already

METHODOLOGY AND SUMMARY OF NEWRECOMMENDATIONS GLOBAL STRATEGY FOR

ASTHMA MANAGEMENT AND PREVENTION: 2009

UPDATE*

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* The Global Strategy for Asthma Management and Prevention (updated 2009), the updated Pocket Guides and the complete list of references examined by the Committee areavailable on the GINA website www.ginasthma.org.

Members (2008-2009): M. FitzGerald, Chair; P. Barnes, N. Barnes, E. Bateman, A. Becker, J. Drazen, R. Lemanske, P. OByrne, K. Ohta, S. Pedersen, E. Pizzichini, H.

Reddel, S. Sullivan, S. Wenzel, H. Zar.

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rigorous method of reviewing the literature and updatingrecommendations that is currently in place. Thecommittee has decided that it would be inappropriate toimplement this methodology for all the recommendationswithin GINA and recommended instead to use the method-ology, selectively, especially where the balance betweenefficacy and cost effectiveness is unclear or where there iscontroversy with regard to the recommendation. TheCommittee applied GRADE to two questions (see sectionD.2) and will continue to explore the use of GRADE-likemethodology for issues that require more in-depthevaluation.

A. Modifications in the text:

Pg 19, right column, insert end of first paragraph: althoughit has been shown that the use of FeNo as a measure ofasthma control does not improve control or enablereduction in dose of inhaled glucocorticosteroid55.Reference 55. Szefler SJ, Mitchell H, Sorkness CA,

Gergen PJ, O'Connor GT, Morgan WJ, et al. Managementof asthma based on exhaled nitric oxide in addition toguideline-based treatment for inner-city adolescents andyoung adults: a randomised controlled trial. Lancet. 2008Sep 20;372(9643):1065-72.

Pg 30, left column, line 6, insert: although there appear tobe differences in response according tosymptom/inflammation phenotype212. Reference 212.Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M,Brightling CE, Wardlaw AJ, Green RH. Cluster analysisand clinical asthma phenotypes. Am J Respir Crit CareMed. 2008 Aug 1;178(3):218-24. Epub 2008 May 14

Pg 30, left column, line 11 from end, insert: A meta-analysis of case-control studies of non-vertebral fracturesin adults using inhaled glucocorticosteroids (BDP orequivalent) indicated that in older adults, the relative risk ofnon-vertebral fractures increases by about 12% for each1000 g/day increase in the dose BDP or equivalent butthat the magnitude of this risk was considerably less thanother common risk factors for fracture in the olderadult213. Reference 213. Weatherall M, James K, ClayJ, Perrin K, Masoli M, Wijesinghe M, Beasley R. Dose-response relationship for risk of non-vertebral fracture withinhaled corticosteroids. Clin Exp Allergy. 2008

Sep;38(9):1451-8. Epub 2008 Jun 3.

Pg 30, right column, last paragraph delete last sentenceand references 52-54 and replace with: No associationwas found between Churg-Strauss syndrome andleukotriene modifiers, after controlling for asthma drug use,although it is not possible to rule out modest associationsgiven that Churg-Strauss syndrome is so rare and sohighly correlated with asthma severity52. New Reference52. Harrold LR, Patterson K, Andrade SE, Dube T, Go

AS, Buist AS, et al. Asthma drug use and thedevelopment of Churg-Strauss syndrome (CSS).Pharmcoepidemiology and Drug Safety. 2007;16:620-26.

Pg 31, left column, paragraph 1, insert: does notincrease the risk of asthma-related hospitalizations214 Reference 214. Jaeschke R, O'Byrne PM, Mejza F, NairP, Lesniak W, Brozek J, Thabane L, Cheng J,Schnemann HJ, Sears MR, Guyatt G. The safety of long-acting beta-agonists among patients with asthma usinginhaled corticosteroids: systematic review andmetaanalysis. Am J Respir Crit Care Med. 2008 Nov15;178(10):1009-16. Epub 2008 Sep 5.

Pg 34, left column, end of paragraph 1, insert: Data on ahuman monoclonal antibody against tumor necrosis factor(TNF)-alpha suggest that the risk benefit equation doesnot favor the use of this class of treatments in severeasthma216. Reference 216. Wenzel SE, Barnes PJ,Bleecker ER, Bousquet J, Busse W, Dahln SE, et al; T03

Asthma Investigators. A randomized, double-blind,placebo-controlled study of tumor necrosis factor-alphablockade in severe persistent asthma. Am J Respir CritCare Med. 2009 Apr 1;179(7):549-58. Epub 2009 Jan 8.

Pg 35, right column, beginning of paragraph 4, insert:Dietary supplements, including selenium therapy197 are notof proven benefit and the use of a low sodium diet as anadjunctive therapy to normal treatment has no additionaltherapeutic benefit in adults with asthma. In addition it hasno effect on bronchial reactivity to methacholine217.Reference 217. Pogson ZE, Antoniak MD, Pacey SJ,Lewis SA, Britton JR, Fogarty AW. Does a low sodium

diet improve asthma control? A randomized controlled trialAm J Respir Crit Care Med. 2008 Jul 15;178(2):132-8.Epub 2008 May 1.

Pg 38, Figure 3.6, delete last statement and insert:Inhaled glucocorticosteroid use has the potential forreducing bone mineral accretion in male childrenprogressing through puberty, but this risk is likely to be outweighed by the ability to reduce the amount of oralcorticosteroids used in these children218. Reference 218.Kelly HW, Van Natta ML, Covar RA, Tonascia J, GreenRP, Strunk RC; CAMP Research Group. Effect of long-term corticosteroid use on bone mineral density in

children: a prospective longitudinal assessment in thechildhood Asthma Management Program (CAMP) study.Pediatrics. 2008 Jul;122(1):e53-61.

Pg 39, left column, end of first paragraph, insert:Montelukast has not been demonstrated to be an effectiveinhaled glucocorticosteroid sparing alternative in childrenwith moderate-to-severe persistent asthma219. Reference219. Strunk RC, Bacharier LB, Phillips BR, Szefler SJ,Zeiger RS, Chinchilli VM, et al.; CARE Network.

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Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate-to-severe childhood asthmastudy. J Allergy Clin Immunol. 2008 Dec;122(6):1138-1144.e4. Epub 2008 Oct 25.

Pg 51, right column, end of last paragraph, insert: Layeducators can be recruited and trained to deliver a discretearea of respiratory care (for example, asthma self-management education) with comparable outcomes tothose achieved by primary care based practice nurses362

(Evidence B).Reference 362. Partridge MR, Caress AL, Brown C,Hennings J, Luker K, Woodcock A, Campbell M. Can laypeople deliver asthma self-management education aseffectively as primary care based practice nurses?Thorax. 2008 Sep;63(9):778-83. Epub 2008 Feb 15.)

Pg 52, right column, last paragraph, delete first sentenceand replace with:Although interventions for enhancingmedication adherence have been developed363, studies of

adults and children with asthma34 have shown that around50% of those on long-term therapy fail to take medicationsas directed at least part of the time. Reference 363.Haynes RB, Ackloo E, Sahota N, McDonald HP, Yao X.Interventions for enhancing medication adherence.Cochrane Database Syst Rev. 2008 Apr 16;(2):CD000011

Pg 55, left column, end of first paragraph, insert: Patientswith well-controlled asthma are less likely to experienceexacerbations than those whose asthma is not well-controlled364.Reference 364: Bateman ED, Bousquet J, Busse WW,Clark TJ, Gul N, Gibbs M, Pedersen S; GOAL Steering

Committee and Investigators. Stability of asthma controlwith regular treatment: an analysis of the Gaining OptimalAsthma controL (GOAL) study. Allergy. 2008Jul;63(7):932-8.

Pg 56, left column, end of third paragraph delete asindicated and insert:Installation of non-polluting, moreeffective heating (heat pump, wood pellet burner, fluedgas) in the homes of children with asthma does notsignificantly improve lung function but does significantlyreduce symptoms of asthma, days off school, healthcareutilization, and visits to a pharmacist365.Reference 365. Howden-Chapman P, Pierse N, Nicholls

S, Gillespie-Bennett J, Viggers H, Cunningham M, et al.Effects of improved home heating on asthma in communitydwelling children: randomized controlled trial. BMJ. 2008Sep 23;337:a1411. doi: 10.1136/bmj.a1411.

Pg 57, left column, end of first paragraph, insert: Betablockers have a proven benefit in the management ofpatients with acute coronary syndromes and for secondaryprevention of coronary events. Data suggest that patientswith asthma who receive newer more cardio-selective beta

blockers, within 24 hours of hospital admission, for anacute coronary event, have lower in-hospital mortalityrates366,367. Reference 366. Babu KS, Gadzik F, HolgateST. Absence of respiratory effects with ivabradine inpatients with asthma. Br J Clin Pharmacol. 2008Jul;66(1):96-101. Epub 2008 Mar 13. Reference 367.Olenchock BA, Fonarow GG, Pan W, Hernandez A,Cannon CP; Get With The Guidelines Steering CommitteeCurrent use of beta blockers in patients with reactiveairway disease who are hospitalized with acute coronarysyndromes. Am J Cardiol. 2009 Feb 1;103(3):295-300.Epub 2008 Nov 19.

Pg 62, left column, last paragraph, delete sentence andreplace with: However, this is more likely to lead to loss ofasthma control137,368 (Evidence B). Reference 368:Godard P, Greillier P, Pigearias B, Nachbaur G,Desfougeres JL, Attali V. Maintaining asthma control inpersistent asthma: comparison of three strategies in a 6-month double-blind randomised study. Respir Med. 2008

Aug;102(8):1124-31. Epub 2008 Jul 7.

Pg 72, left column, end of third paragraph, insert: Adultswith asthma may be at increased risk of seriouspneumococcal disease370. Reference 370. Juhn YJ, KitaH, Yawn BP, Boyce TG, Yoo KH, McGree ME, Weaver ALWollan P, Jacobson RM. Increased risk of seriouspneumococcal disease in patients with asthma. J AllergyClin Immunol. 2008 Oct;122(4):719-23. Epub 2008 Sep13.

Pg 89, right column, first paragraph, insert: Use ofadministrative datasets (e.g., dispensing records) or urgen

health care utilization can help to identify at-risk patients orto audit the quality of health care23. Reference 23.Bereznicki BJ, Peterson GM, Jackson SL, Walters EH,Fitzmaurice KD, Gee PR. Data-mining of medicationrecords to improve asthma management. Med J Aust.2008 Jul 7;189(1):21-5.

B. References that provided confirmation or update ofprevious recommendations:

Pg 24: Right column, replace reference 32. Horvath I,Hunt J, Barnes PJ, Alving K, Antczak A, Baraldi E, et al.Exhaled breath condensate: methodological

recommendations and unresolved questions. Eur Respir J2005;26:523-48.

Pg 30: Left column, insert reference 211. O'Byrne PM,Naya IP, Kallen A, Postma DS, Barnes PJ. Increasingdoses of inhaled corticosteroids compared to adding long-acting inhaled beta2-agonists in achieving asthma control.Chest. 2008 Dec;134(6):1192-9. Epub 2008 Aug 8.

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Pg 31: right column, insert reference 215. Cates CJ,Cates MJ. Regular treatment with salmeterol for chronicasthma: serious adverse events. Cochrane Database ofSystematic Reviews2008, Issue 3. Art. No.: CD006363

Pg 70, right column, second paragraph, insert reference369. Tata LJ, Lewis SA, McKeever TM, Smith CJ, DoyleP, Smeeth L, Gibson JE, Hubbard RB. Effect of maternalasthma, exacerbations and asthma medication use oncongenital malformations in offspring: a UK population-based study. Thorax. 2008 Nov;63(11):981-7. Epub 2008Aug 4.

Pg 70, right column, second paragraph, replace reference268. Bakhireva LN, Schatz M, Jones KL, Chambers CD;Organization of Teratology Information SpecialistsCollaborative Research Group. Asthma control duringpregnancy and the risk of preterm delivery or impairedfetal growth. Ann Allergy Asthma Immunol. 2008Aug;101(2):137-43

Pg 71, left column, third paragraph, replace reference 279.Shaaban R, Zureik M, Soussan D, Neukirch C, Heinrich J,Sunyer J, et al. Rhinitis and onset of asthma: alongitudinal population-based study. Lancet. 2008 Sep20;372(9643):1049-57.

Pg 78, delete reference 150.

C. Changes or modifications to the text.

Pg xiv xvii: Delete section Executive Summary:Managing Asthma in Children 5 Years and Younger. Thishas been replaced with new report Global Strategy for

Asthma Management and Prevention in Children 5 Yearsand Younger.

Pg 28, left column line 10, delete: and other systemicsteroid-sparing therapies.

Pg 29, Figure 3-1:Change Fluticasone to Fluticasonepropionate.

Pg 31, left column, end of paragraph 2, insert: SeeAppendix B, GINA Pocket Guide updated 2009 forinformation on Asthma Combination Medications ForAdults and Children 5 Years and Older.

Pg 31, left column, beginning of paragraph 3, insert:when used as a combination medication with inhaledglucocorticosteroids

Pg 37, Figure 3-4: Change Fluticasone to Fluticasonepropionate.

Pg 59, Figure 4.3-2: Modifications to clarify wording onFigure; modify lower segment to read Global Strategy for

Asthma Management and Prevention in Children 5 Yearsand Younger. Available at www.ginasthma.org

Pg 61, right column, second paragraph: Change EvidenceA to Evidence B.

Pg 70, right column, second paragraph, first phrase deleteand replace with: Although there is a general concernabout the use of any medication in pregnancy,.

D. Committee recommended changes:

1. Asthma Control:Based on a number of recentpublications, the Committee recommended significantchanges to the section on Classification of Asthma, pages22 23. Figure 2-4 has been deleted. Former Figure 2-5(now appears as Figure 2-4), has been modified. Thismodified Figure also appears on page 58 (as Figure 4.3-1).

2. Grading Evidence: The GINA Science Committee isdeveloping a system to identify recommendations wherethere maybe controversy or debate between efficacy andcost. In addition there are some recommendations thathave a less robust evidence base. In this context we see apossible role for the GRADE methodology providing aframework collate the evidence and create evidencetables. To assess the feasibility of this approach twoquestions were reviewed in 2009 to begin the work:

a. In adults with asthma, does monoclonal anti-IgE,omalizumab, compared to placebo improve patient outcomes?

b. In adults with acute exacerbations of asthma, doesintravenous magnesium sulphate compared to placeboimprove patient important outcomes?

Evidence tables were produced and are being evaluatedand the results from this work are being prepared forpublication. Further information will be provided in the2010 update.

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Asthma is a serious public health problem throughout theworld, affecting people of all ages. When uncontrolled,asthma can place severe limits on daily life, and is

sometimes fatal.

In 1993, the Global Initiative for Asthma (GINA) wasformed. Its goals and objectives were described in a 1995

NHLBI/WHO Workshop Report, Global Strategy forAsthma Management and Prevention. This Report(revised in 2002), and its companion documents, have

been widely distributed and translated into manylanguages. A network of individuals and organizations

interested in asthma care has been created and severalcountry-specific asthma management programs have

been initiated. Yet much work is still required to reducemorbidity and mortality from this chronic disease.

In January 2004, the GINA Executive Committeerecommended that the Global Strategy for Asthma

Management and Preventionbe revised to emphasizeasthma management based on clinical control, rather than

classification of the patient by severity. This importantparadigm shift for asthma care reflects the progress thathas been made in pharmacologic care of patients. Many

asthma patients are receiving, or have received, someasthma medications. The role of the health care

professional is to establish each patients current level oftreatment and control, then adjust treatment to gain and

maintain control. This means that asthma patients should

experience no or minimal symptoms (including at night),have no limitations on their activities (including physical

exercise), have no (or minimal) requirement for rescuemedications, have near normal lung function, and

experience only very infrequent exacerbations.

FUTURE CHALLENGES

In spite of laudable efforts to improve asthma care over the

past decade, a majority of patients have not benefited fromadvances in asthma treatment and many lack even the

rudiments of care. A challenge for the next several yearsis to work with primary health care providers and public

health officials in various countries to design, implement,and evaluate asthma care programs to meet local needs.

The GINA Executive Committee recognizes that this is adifficult task and, to aid in this work, has formed severalgroups of global experts, including: a Dissemination Task

Group; the GINA Assembly, a network of individuals whocare for asthma patients in many different health care

settings; and regional programs (the first two being GINAMesoamerica and GINA Mediterranean). These efforts

aim to enhance communication with asthma specialists,primary-care health professionals, other health careworkers, and patient support organizations. The Executive

Committee continues to examine barriers to implementation

of the asthma management recommendations, especiallythe challenges that arise in primary-care settings and indeveloping countries.

While early diagnosis of asthma and implementation ofappropriate therapy significantly reduce the socioeconomic

burdens of asthma and enhance patients quality of life,medications continue to be the major component of the

cost of asthma treatment. For this reason, the pricing ofasthma medications continues to be a topic for urgent

need and a growing area of research interest, as this hasimportant implications for the overall costs of asthmamanagement.

Moreover, a large segment of the worlds population lives

in areas with inadequate medical facilities and meagerfinancial resources. The GINA Executive Committee

recognizes that fixed international guidelines and rigidscientific protocols will not work in many locations. Thus,the recommendations found in this Report must be

adapted to fit local practices and the availability of healthcare resources.

As the GINA Committees expand their work, every effort

will be made to interact with patient and physician groups

at national, district, and local levels, and in multiple healthcare settings, to continuously examine new and innovative

approaches that will ensure the delivery of the best asthmacare possible. GINA is a partner organization in a program

launched in March 2006 by the World Health Organization,the Global Alliance Against Chronic Respiratory Diseases

(GARD). Through the work of the GINA Committees, andin cooperation with GARD initiatives, progress towardbetter care for all patients with asthma should be

substantial in the next decade.

METHODOLOGY

A. Preparation of yearly updates: Immediatelyfollowing the release of an updated GINA Report in 2002,

the Executive Committee appointed a GINA ScienceCommittee, charged with keeping the Report up-to-dateby reviewing published research on asthma management

and prevention, evaluating the impact of this research onthe management and prevention recommendations in the

GINA documents, and posting yearly updates of thesedocuments on the GINA website. The first update was

INTRODUCTION

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posted in October 2003, based on publications fromJanuary 2000 through December 2002. A second update

appeared in October 2004, and a third in October 2005,each including the impact of publications from January

through December of the previous year.

The process of producing the yearly updates began with aPub Med search using search fields established by theCommittee: 1) asthma, All Fields, All ages, only items with

abstracts, Clinical Trial, Human, sorted by Authors;and2) asthma AND systematic, All fields, ALL ages, only items

with abstracts, Human, sorted by Author. In addition,peer-reviewed publications not captured by Pub Med could

be submitted to individual members of the Committeeproviding an abstract and the full paper were submitted in(or translated into) English.

All members of the Committee received a summary of

citations and all abstracts. Each abstract was assigned to

two Committee members, and an opportunity to provide anopinion on any single abstract was offered to all members.Members evaluated the abstract or, up to her/hisjudgment, the full publication, by answering specific written

questions from a short questionnaire, indicating whetherthe scientific data presented affected recommendations in

the GINA Report. If so, the member was asked tospecifically identify modifications that should be made.

The entire GINA Science Committee met on a regularbasis to discuss each individual publication that was

judged by at least one member to have an impact onasthma management and prevention recommendations,and to reach a consensus on the changes in the Report.

Disagreements were decided by vote.

The publications that met the search criteria for eachyearly update (between 250 and 300 articles per year)

mainly affected the chapters related to clinicalmanagement. Lists of the publications considered by theScience Committee each year, along with the yearly

updated reports, are posted on the GINA website,www.ginasthma.org.

B. Preparation of new 2006 report: In January 2005,the GINA Science Committee initiated its work on this new

report. During a two-day meeting, the Committeeestablished that the main theme of the new report should

be the control of asthma. A table of contents wasdeveloped, themes for each chapter identified, and writing

teams formed. The Committee met in May and September2005 to evaluate progress and to reach consensus on

messages to be provided in each chapter. Throughout itswork, the Committee made a commitment to develop adocument that would: reach a global audience, be based

on the most current scientific literature, and be as concise

as possible, while at the same time recognizing that one ofthe values of the GINA Report has been to provide

background information about asthma management andthe scientific information on which management

recommendations are based.

In January 2006, the Committee met again for a two-daysession during which another in-depth evaluation of eachchapter was conducted. At this meeting, members

reviewed the literature that appeared in 2005using thesame criteria developed for the update process. The list

of 285 publications from 2005 that were considered isposted on the GINA website. At the January meeting, it

was clear that work remaining would permit the report tobe finished during the summer of 2006 and, accordingly,the Committee requested that as publications appeared

throughout early 2006, they be reviewed carefully for theirimpact on the recommendations. At the Committees next

meeting in May, 2006 publications meeting the search

criteria were considered and incorporated into the currentdrafts of the chapters, where appropriate. A final meetingof the Committee was held in September 2006, at whichpublications that appear prior to July 31, 2006 were

considered for their impact on the document.

Periodically throughout the preparation of this report,representatives from the GINA Science Committee have

met with members of the GINA Assembly (May andSeptember, 2005 and May 2006) to discuss the overall

theme of asthma control and issues specific to each of thechapters. The GINA Assembly includes representativesfrom over 50 countries and many participated in these

interim discussions. In addition, members of the Assemblywere invited to submit comments on a DRAFT document

during the summer of 2006. Their comments, along withcomments received from several individuals who were

invited to serve as reviewers, were considered by theCommittee in September, 2006.

Summary of Major Changes

The major goal of the revision was to present informationabout asthma management in as comprehensive manner

as possible but not in the detail that would normally be

found in a textbook. Every effort has been made to selectkey references, although in many cases, several other

publications could be cited. The document is intended tobe a resource; other summary reports will be prepared,

including a Pocket Guide specifically for the care of infantsand young children with asthma.

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Some of the major changes that have been made in thisreport include:

1. Every effort has been made to produce a morestreamlined document that will be of greater use to busyclinicians, particularly primary care professionals. The

document is referenced with the up-to-date sources so thatinterested readers may find further details on varioustopics that are summarized in the report.

2. The whole of the document now emphasizes asthmacontrol. There is now good evidence that the clinicalmanifestations of asthmasymptoms, sleep disturbances,limitations of daily activity, impairment of lung function, anduse of rescue medicationscan be controlled withappropriate treatment.

3. Updated epidemiological data, particularly drawn fromthe report Global Burden of Asthma, are summarized.

Although from the perspective of both the patient andsociety the cost to control asthma seems high, the cost ofnot treating asthma correctly is even higher.

4. The concept of difficult-to-treat asthma is introduced anddeveloped at various points throughout the report. Patientswith difficult-to-treat asthma are often relatively insensitiveto the effects of glucocorticosteroid medications, and maysometimes be unable to achieve the same level of controlas other asthma patients.

5. Lung function testing by spirometry or peak expiratoryflow (PEF) continues to be recommended as an aid to

diagnosis and monitoring. Measuring the variabilityofairflow limitation is given increased prominence, as it is key toboth asthmadiagnosisand theassessment of asthmacontrol.

6. The previous classification of asthma by severity intoIntermittent, Mild Persistent, Moderate Persistent, and SeverePersistent is now recommended only for research purposes.

7. Instead, the document now recommends a classificationof asthma by level of control: Controlled, Partly Controlled,or Uncontrolled. This reflects an understanding that asthmaseverity involves not only the severity of the underlyingdisease but also its responsiveness to treatment, and that

severity is not an unvarying feature of an individualpatients asthma but may change over months or years.

8. Throughout the report, emphasis is placed on theconcept that the goal of asthma treatment is to achieveand maintain clinical control. Asthma control is defined as:

No (twice or less/week) daytime symptoms No limitations of daily activities, including exercise No nocturnal symptoms or awakening because of asthma

No (twice or less/week) need for reliever treatment

Normal or near-normal lung function results No exacerbations

9. Emphasis is given to the concept that increased use,

especially daily use, of reliever medication is a warning of

deterioration of asthma control and indicates the need toreassess treatment.

10. The roles in therapy of several medications have

evolved since previous versions of the report: Recent data indicating a possible increased risk of

asthma-related death associated with the use of long-acting2-agonists in a small group of individuals hasresulted in increased emphasis on the message that

long-acting2-agonists should not be used asmonotherapy in asthma, and must only be used in

combination with an appropriate dose of inhaledglucocorticosteroid.

Leukotriene modifiers now have a more prominentrole as controller treatment in asthma, particularly inadults. Long-acting oral2-agonists alone are no

longer presented as an option for add-on treatment atany step of therapy, unless accompanied by inhaled

glucocorticosteroids. Monotherapy with cromones is no longer given as an

alternative to monotherapy with a low dose of inhaledglucocorticosteroids in adults.

Some changes have been made to the tables of

equipotent daily doses of inhaled glucocorticosteroidsfor both children and adults.

11. The six-part asthma management program detailed in

previous versions of the report has been changed. Thecurrent program includes the following five components:

Component 1. Develop Patient/Doctor Partnership

Component 2. Identify and Reduce Exposure to RiskFactors

Component 3. Assess, Treat, and Monitor AsthmaComponent 4. Manage Asthma Exacerbations

Component 5. Special Considerations

12. The inclusion of Component 1 reflects the fact that

effective management of asthma requires the development

of a partnership between the person with asthma and hisor her health care professional(s) (and parents/caregivers,in the case of children with asthma). The partnership is

formed and strengthened as patients and their health careprofessionals discuss and agree on the goals of treatment,

develop a personalized, written self-management actionplan including self-monitoring, and periodically review thepatients treatment and level of asthma control. Education

remains a key element of all doctor-patient interactions.

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13. Component 3 presents an overall concept for asthmamanagement oriented around the new focus on asthmacontrol. Treatment is initiated and adjusted in a continuous

cycle (assessing asthma control, treating to achievecontrol, and monitoring to maintain control) driven by the

patients level of asthma control.

14. Treatment options are organized into five Stepsreflecting increasing intensity of treatment (dosages and/ornumber of medications) required to achieve control. At all

Steps, a reliever medication should be provided for as-needed use. At Steps 2through 5, a variety of controller

medications are available.

15. If asthma is not controlled on the current treatmentregimen, treatment should be stepped up until control isachieved. When control is maintained, treatment can be

stepped down in order to find the lowest step and dose oftreatment that maintains control.

16. Although each component contains management

advice for all age categories where these are consideredrelevant, special challenges must be taken into account inmaking recommendations for managing asthma in children

in the first 5 years of life. Accordingly, an ExecutiveSummary has been preparedand appears at the end of

this introductionthat extracts sections on diagnosis andmanagement for this very young age group.

17. It has been demonstrated in a variety of settings thatpatient care consistent with evidence-based asthma guide-

lines leads to improved outcomes. However, in order toeffect changes in medical practice and consequent

improvements in patient outcomes, evidence-basedguidelines must be implemented and disseminated at

national and local levels. Thus, a chapter has beenadded on implementation of asthma guidelines in health

systems that details the process and economics ofguideline implementation.

LEVELS OF EVIDENCE

In this document, levels of evidence are assigned tomanagement recommendations where appropriate in

Chapter 4, the Five Components of Asthma Management.Evidence levels are indicated in boldface type enclosed inparentheses after the relevant statemente.g., (Evidence A).The methodological issues concerning the use of evidencefrom meta-analyses were carefully considered1.

This evidence level scheme (Table A) has been used inprevious GINA reports, and was in use throughout thepreparation of this document. The GINA ScienceCommittee was recently introduced to a new approach to

evidence levels2 and plans to review and consider thepossible introduction of this approach in future reports andextending it to evaluative and diagnostic aspects of care.

REFERENCES1. Jadad AR, Moher M, Browman GP, Booker L, Sigouis C

Fuentes M, et al. Systematic reviews and meta-analyseson treatment of asthma: critical evaluation. BMJ

2000;320:537-40.2. Guyatt G, Vist G, Falck-Ytter Y, Kunz R, Magrini N,

Schunemann H. An emerging consensus on gradingrecommendations? Available from URL:http://www.evidence-basedmedicine.com.

Table A. Description of Levels of Evidence

Evidence Sources of DefinitionCategory Evidence

A

B

C

D

Randomized controlled trials(RCTs). Rich body of data.

Evidence is from endpoints ofwell designed RCTs thatprovide a consistent pattern offindings in the population forwhich the recommendationis made. Category A requiressubstantial numbers of studiesinvolving substantial numbersof participants.

Randomized controlled trials(RCTs). Limited body of data.

Evidence is from endpoints ofintervention studies thatinclude only a limited numberof patients, posthoc orsubgroup analysis of RCTs,ormeta-analysis of RCTs. In

general, Category B pertainswhen few randomized trialsexist, they are small in size,they were undertaken in apopulation that differs from thetarget population of the recom-mendation,or the results aresomewhat inconsistent.

Nonrandomized trials.Observational studies.

Evidence is from outcomes ofuncontrolled or nonrandomizedtrials or from observationalstudies.

Panel consensus judgment. This category is used only incaseswhere the provision ofsome guidancewas deemedvaluable but the clinical

literature addressing thesubject was insufficient tojustify placement in one of theother categories. ThePanelConsensus is based onclinical experience orknowledge that does not meetthe above-listed criteria.

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CHAPTER

1

DEFINITION

AND

OVERVIEW

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This chapter covers several topics related to asthma,including definition, burden of disease, factors that influence

the risk of developing asthma, and mechanisms. It is notintended to be a comprehensive treatment of these topics,but rather a brief overview of the background that informs

the approach to diagnosis and management detailed insubsequent chapters. Further details are found in the

reviews and other references cited at the end of the chapter.

DEFINITION

Asthma is a disorder defined by its clinical, physiological,and pathological characteristics. The predominant feature

of the clinical history is episodic shortness of breath,particularly at night, often accompanied by cough.

Wheezing appreciated on auscultation of the chest is themost common physical finding.

The main physiological feature of asthma is episodic airwayobstruction characterized by expiratory airflow limitation.

The dominant pathological feature is airway inflammation,

sometimes associated with airway structural changes.

Asthma has significant genetic and environmental

components, but since its pathogenesis is not clear, muchof its definition is descriptive. Based on the functional

consequences of airway inflammation, an operationaldescription of asthma is:

Asthma is a chronic inflammatory disorder of the airwaysin which many cells and cellular elements play a role.

The chronic inflammation is associated with airwayhyperresponsiveness that leads to recurrent episodes of

wheezing, breathlessness, chest tightness, and coughing,

particularly at night or in the early morning. Theseepisodes are usually associated with widespread, but

variable, airflow obstruction within the lung that is oftenreversible either spontaneously or with treatment.

Because there is no clear definition of the asthma

phenotype, researchers studying the development of thiscomplex disease turn to characteristics that can bemeasured objectively, such as atopy (manifested as the

presence of positive skin-prick tests or the clinicalresponse to common environmental allergens), airway

hyperresponsiveness (the tendency of airways to narrowexcessively in response to triggers that have little or no

effect in normal individuals), and other measures ofallergic sensitization. Although the association betweenasthma and atopy is well established, the precise links

between these two conditions have not been clearly andcomprehensively defined.

There is now good evidence that the clinical manifestations

of asthmasymptoms, sleep disturbances, limitations ofdaily activity, impairment of lung function, and use ofrescue medicationscan be controlled with appropriate

treatment. When asthma is controlled, there should be nomore than occasional recurrence of symptoms and severe

exacerbations should be rare1

.

KEY POINTS:

Asthma is a chronic inflammatory disorder of the

airways in which many cells and cellular elementsplay a role. The chronic inflammation is associatedwith airway hyperresponsiveness that leads to

recurrent episodes of wheezing, breathlessness,chest tightness, and coughing, particularly at night

or in the early morning. These episodes are usuallyassociated with widespread, but variable, airflow

obstruction within the lung that is often reversibleeither spontaneously or with treatment.

Clinical manifestations of asthma can be controlledwith appropriate treatment. When asthma is

controlled, there should be no more than occasionalflare-ups and severe exacerbations should be rare.

Asthma is a problem worldwide, with an estimated300 million affected individuals.

Although from the perspective of both the patient and

society the cost to control asthma seems high, thecost of not treating asthma correctly is even higher.

A number of factors that influence a persons risk ofdeveloping asthma have been identified. These can

be divided into host factors (primarily genetic) andenvironmental factors.

The clinical spectrum of asthma is highly variable,

and different cellular patterns have been observed,but the presence of airway inflammation remains aconsistent feature.

2 DEFINITION AND OVERVIEW

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THE BURDEN OF ASTHMA

Prevalence, Morbidity, and Mortality

Asthma is a problem worldwide, with an estimated 300

million affected individuals2,3. Despite hundreds of reports

on the prevalence of asthma in widely differingpopulations, the lack of a precise and universally accepteddefinition of asthma makes reliable comparison of reported

prevalence from different parts of the world problematic.Nonetheless, based on the application of standardized

methods to measure the prevalence of asthma andwheezing illness in children3 and adults4, it appears thatthe global prevalence of asthma ranges from 1% to 18% of

the population in different countries (Figure 1-1)2,3. Thereis good evidence that international differences in asthma

symptom prevalence have been reduced, particularly inthe 13-14 year age group, with decreases in prevalence in

North America and Western Europe and increases in

prevalence in regions where prevalence was previouslylow. Although there was little change in the overall

prevalence of current wheeze, the percentage of childrenreported to have had asthma increased significantly, possi-

bly reflecting greater awareness of this condition and/orchanges in diagnostic practice. The increases in asthma

symptom prevalence in Africa, Latin America and parts ofAsia indicate that the global burden of asthma iscontinuing to rise, but the global prevalence differences

are lessening126. The World Health Organization hasestimated that 15 million disability-adjusted life years

(DALYs) are lost annually due to asthma, representing 1%of the total global disease burden2. Annual worldwide

deaths from asthma have been estimated at 250,000 andmortality does not appear to correlate well with prevalence(Figure 1-1)2,3. There are insufficient data to determine thelikely causes of the described variations in prevalencewithin and between populations.

Social and Economic Burden

Social and economic factors are integral to understanding

asthma and its care, whether viewed from the perspectiveof the individual sufferer, the health care professional, orentities that pay for health care. Absence from school and

days lost from work are reported as substantial social andeconomic consequences of asthma in studies from the

Asia-Pacific region, India, Latin America, the UnitedKingdom, and the United States9-12.

The monetary costs of asthma, as estimated in a varietyof health care systems including those of the United

States13-15 and the United Kingdom16 are substantial.In analyses of economic burden of asthma, attention

needs to be paid to both direct medical costs (hospitaladmissions and cost of medications) and indirect, non-

medical costs (time lost from work, premature death)17.For example, asthma is a major cause of absence from

work in many countries4-6,121, including Australia, Sweden,the United Kingdom, and the United States16,18-20.Comparisons of the cost of asthma in different regions

lead to a clear set of conclusions:

The costs of asthma depend on the individual patientslevel of control and the extent to which exacerbations

are avoided.

Emergency treatment is more expensive than planned

treatment.

Non-medical economic costs of asthma are substantial.

Guideline-determined asthma care can be cost effective.

Families can suffer from the financial burden of treatingasthma.

Although from the perspective of both the patient andsociety the cost to control asthma seems high, the cost of

not treating asthma correctly is even higher122. Propertreatment of the disease poses a challenge for individuals,

health care professionals, health care organizations, andgovernments. There is every reason to believe that thesubstantial global burden of asthma can be dramatically

reduced through efforts by individuals, their health careproviders, health care organizations, and local and

national governments to improve asthma control.

Detailed reference information about the burden of asthmacan be found in the report Global Burden of Asthma* .Further studies of the social and economic burden of

asthma and the cost effectiveness of treatment are neededin both developed and developing countries.

DEFINITION AND OVERVIEW 3

Figure 1-1. Asthma Prevalence and Mortality2, 3

Permission for use of this figure obtained from J. Bousquet.*(http://www.ginasthma.org/ReportItem.asp?l1=2&l2=2&intId=94).

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FACTORS INFLUENCING THE

DEVELOPMENT AND EXPRESSION

OF ASTHMA

Factors that influence the risk of asthma can be dividedinto those that cause the development of asthma andthose that trigger asthma symptoms; some do both.

The former include host factors (which are primarilygenetic) and the latter are usually environmental factors

(Figure 1-2)21. However, the mechanisms whereby theyinfluence the development and expression of asthma arecomplex and interactive. For example, genes likely

interact both with other genes and with environmentalfactors to determine asthma susceptibility22,23. In addition,

developmental aspectssuch as the maturation of theimmune response and the timing of infectious exposures

during the first years of lifeare emerging as important

factors modifying the risk of asthma in the geneticallysusceptible person.

Additionally, some characteristics have been linked to anincreased risk for asthma, but are not themselves truecausal factors. The apparent racial and ethnic differences

in the prevalence of asthma reflect underlying geneticvariances with a significant overlay of socioeconomic and

environmental factors. In turn, the links between asthmaand socioeconomic statuswith a higher prevalence of

asthma in developed than in developing nations, in poor

compared to affluent populations in developed nations,and in affluent compared to poor populations in developing

nationslikely reflect lifestyle differences such asexposure to allergens, access to health care, etc.

Much of what is known about asthma risk factors comesfrom studies of young children. Risk factors for the

development of asthma in adults, particularly de novoinadults who did not have asthma in childhood, are less

well defined.

The lack of a clear definition for asthma presents asignificant problem in studying the role of different riskfactors in the development of this complex disease,

because the characteristics that define asthma (e.g.,airway hyperresponsiveness, atopy, and allergic

sensitization) are themselves products of complexgene-environment interactions and are therefore both

features of asthma and risk factors for the developmentof the disease.

Host Factors

Genetic. Asthma has a heritable component, but it is notsimple. Current data show that multiple genes may be

involved in the pathogenesis of asthma24,25, and differentgenes may be involved in different ethnic groups. Thesearch for genes linked to the development of asthma has

focused on four major areas: production of allergen-specific IgE antibodies (atopy); expression of airway

hyperresponsiveness; generation of inflammatory

mediators, such as cytokines, chemokines, and growthfactors; and determination of the ratio between Th1 andTh2 immune responses (as relevant to the hygiene

hypothesis of asthma)26.

Family studies and case-control association analyses have

identified a number of chromosomal regions associatedwith asthma susceptibility. For example, a tendency to

produce an elevated level of total serum IgE is co-inheritedwith airway hyperresponsiveness, and a gene (or genes)

governing airway hyperresponsiveness is located near amajor locus that regulates serum IgE levels onchromosome 5q27. However, the search for a specific

gene (or genes) involved in susceptibility to atopy orasthma continues, as results to date have been

inconsistent24,25.

In addition to genes that predispose to asthma there aregenes that are associated with the response to asthmatreatments. For example, variations in the gene encodingthe beta-adrenoreceptor have been linked to differences in


Figure 1-2. Factors Influencing the Developmentand Expression of Asthma

HOST FACTORSGenetic, e.g.,

Genes pre-disposing to atopy Genes pre-disposing to airway hyperresponsiveness

ObesitySex

ENVIRONMENTAL FACTORSAllergens

Indoor: Domestic mites, furred animals (dogs, cats,mice), cockroach allergen, fungi, molds, yeasts

Outdoor: Pollens, fungi, molds, yeastsInfections (predominantly viral)

Occupational sensitizersTobacco smoke Passive smoking

Active smokingOutdoor/Indoor Air Pollution

Diet

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subjects responses to 2-agonists28. Other genes of

interest modify the responsiveness to glucocorticosteroids29

and leukotriene modifiers30. These genetic markers willlikely become important not only as risk factors in thepathogenesis of asthma but also as determinants ofresponsiveness to treatment28,30-33.

Obesity. Obesity has also been shown to be a risk factorfor asthma. Certain mediators such as leptins may affectairway function and increase the likelihood of asthmadevelopment34,35.

Sex. Male sex is a risk factor for asthma in children. Priorto the age of 14, the prevalence of asthma is nearly twiceas great in boys as in girls36. As children get older thedifference between the sexes narrows, and by adulthoodthe prevalence of asthma is greater in women than in men.The reasons for this sex-related difference are not clear.However, lung size is smaller in males than in females at

birth37

but larger in adulthood.

Environmental Factors

There is some overlap between environmental factors thatinfluence the risk of developing asthma, and factors thatcause asthma symptomsfor example, occupationalsensitizers belong in both categories. However, there aresome important causes of asthma symptomssuch as airpollution and some allergenswhich have not been clearlylinked to the development of asthma. Risk factors thatcause asthma symptoms are discussed in detail in

Chapter 4.2.

Allergens. Although indoor and outdoor allergens are wellknown to cause asthma exacerbations, their specific rolein the development of asthma is still not fully resolved.Birth-cohort studies have shown that sensitization to housedust mite allergens, cat dander, dog dander38,39, andAspergillusmold40 are independent risk factors for asthma-like symptoms in children up to 3 years of age. However,the relationship between allergen exposure andsensitization in children is not straightforward. It dependson the allergen, the dose, the time of exposure, the childsage, and probably genetics as well.

For some allergens, such as those derived from housedust mites and cockroaches, the prevalence ofsensitization appears to be directly correlated withexposure38,41. However, although some data suggest thatexposure to house dust mite allergens may be a causalfactor in the development of asthma42, other studies havequestioned this interpretation43,44. Cockroach infestationhas been shown to be an important cause of allergicsensitization, particularly in inner-city homes45.

In the case of dogs and cats, some epidemiologic studieshave found that early exposure to these animals may protecta child against allergic sensitization or the development ofasthma46-48, but others suggest that such exposure mayincrease the risk of allergic sensitization47,49-51. This issueremains unresolved.

The prevalence of asthma is reduced in children raised ina rural setting, which may be linked to the presence ofendotoxin in these environments52.

Infections. During infancy, a number of viruses have beenassociated with the inception of the asthmatic phenotype.Respiratory syncytial virus (RSV) and parainfluenza virusproduce a pattern of symptoms including bronchiolitis thatparallel many features of childhood asthma53,54. A numberof long-term prospective studies of children admitted to thehospital with documented RSV have shown thatapproximately 40% will continue to wheeze or haveasthma into later childhood53. On the other hand, evidencealso indicates that certain respiratory infections early in lifeincluding measles and sometimes even RSV, may protectagainst the development of asthma55,56. The data do notallow specific conclusions to be drawn. Parasite infectionsdo not in general protect against asthma, but infection withhookworm may reduce the risk123.

The hygiene hypothesis of asthma suggests that exposureto infections early in life influences the development of achilds immune system along a nonallergic pathway, leadingto a reduced risk of asthma and other allergic diseases.Although the hygiene hypothesis continues to be investigated,thismechanism may explain observed associations betweenfamily size, birth order, day-care attendance, and the risk ofasthma. For example, young children with older siblings andthose who attend day care are at increased risk of infections,but enjoy protection against the development of allergicdiseases, including asthma later in life57-59.

The interaction between atopy and viral infections appearsto be a complex relationship60, in which the atopic state caninfluence the lower airway response to viral infections, viralinfections can then influence the development of allergicsensitization, and interactions can occur when individualsare exposed simultaneously to both allergens and viruses.

Occupational sensitizers. Over 300 substances havebeen associated with occupational asthma61-65, which isdefined as asthma caused by exposure to an agentencountered in the work environment. These substancesinclude highly reactive small molecules such asisocyanates, irritants that may cause an alteration inairway responsiveness, known immunogens such asplatinum salts, and complex plant and animal biologicalproducts that stimulate the production of IgE (Figure 1-3).


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Occupational asthma arises predominantly in adults66, 67,and occupational sensitizers are estimated to cause about

1 in 10 cases of asthma among adults of working age68.Asthma is the most common occupational respiratory

disorder in industrialized countries69. Occupationsassociated with a high risk for occupational asthma include

farming and agricultural work, painting (including spraypainting), cleaning work, and plastic manufacturing62.

Most occupational asthma is immunologically mediatedand has a latency period of months to years after the onset

of exposure70. IgE-mediated allergic reactions and cell-mediated allergic reactions are involved71,72.

Levels above which sensitization frequently occurs havebeen proposed for many occupational sensitizers.

However, the factors that cause some people but not

others to develop occupational asthma in response to the

same exposures are not well identified. Very highexposures to inhaled irritants may cause irritant induced

asthma (formerly called the reactive airways dysfunctionalsyndrome) even in non-atopic persons. Atopy and

tobacco smoking may increase the risk of occupational

sensitization, but screening individuals for atopy is oflimited value in preventing occupational asthma73. The

most important method of preventing occupational asthmais elimination or reduction of exposure to occupational

sensitizers.

Tobacco smoke. Tobacco smoking is associated withaccelerated decline of lung function in people with asthma,increases asthma severity, may render patients less

responsive to treatment with inhaled74,124 and systemic75

glucocorticosteroids, and reduces the likelihood of asthma

being controlled76.

Exposure to tobacco smoke both prenatally and after birthis associated with measurable harmful effects including agreater risk of developing asthma-like symptoms in early

childhood. However, evidence of increased risk of allergicdiseases is uncertain77,78. Distinguishing the independent

contributions of prenatal and postnatal maternal smokingis problematic79. However, studies of lung function

immediately after birth have shown that maternal smokingduring pregnancy has an influence on lung development37.Furthermore, infants of smoking mothers are 4 times more

likely to develop wheezing illnesses in the first year of life80.In contrast, there is little evidence (based on meta-

analysis) that maternal smoking during pregnancy has an

effect on allergic sensitization78. Exposure toenvironmental tobacco smoke (passive smoking)increases the risk of lower respiratory tract illnesses in

infancy81 and childhood82.

Outdoor/indoor air pollution. The role of outdoor air

pollution in causing asthma remains controversial83.Children raised in a polluted environment have diminished

lung function84, but the relationship of this loss of functionto the development of asthma is not known.

Outbreaks of asthma exacerbations have been shown tooccur in relationship to increased levels of air pollution,

and this may be related to a general increase in the levelof pollutants or to specific allergens to which individuals

are sensitized85-87. However, the role of pollutants in thedevelopment of asthma is less well defined. Similar

associations have been observed in relation to indoorpollutants, e.g., smoke and fumes from gas and biomassfuels used for heating and cooling, molds, and cockroach

infestations.


Figure 1-3. Examples of Agents Causing Asthma inSelected Occupations*

Occupation/occupational field Agent

Animal and Plant Proteins

Bakers Flour, amylase

Dairy farmers Storage mites

Detergent manufacturing Bacillus subtilisenzymes

Electrical s oldering Colophony ( pine r esin)

Farmers Soybean dust

Fish food manufacturing Midges, parasites

Food processing Coffee bean dust, meat tenderizer, tea, shellfish,amylase, egg proteins, pancreatic enzymes,papain

Granary workers Storage mites, Aspergillus, indoor ragweed, grass

Health care workers Psyllium, latex

Laxative manufacturing Ispaghula,psyllium

Poultry f armers Poultry mites, d roppings, f eathers

Research workers, veterinarians Locusts, dander, urine proteins

Sawmill workers, carpenters Wood dust (western red cedar, oak, mahogany,zebrawood, redwood, Lebanon cedar, Africanmaple, eastern white cedar)

Shipping w orkers Grain dust ( molds, i nsects, g rain)

Silk workers Silk worm moths and larvae

Inorganic chemicals

Beauticians Persulfate

Plating Nickel salts

Refinery workers Platinum salts, vanadium

Organic chemicals

Automobile painting Ethanolamine, dissocyanates

Hospital workers Disinfectants (sulfathiazole, chloramines,formaldehyde, glutaraldehyde), latex

Manufacturing Antibiotics, piperazine, methyldopa, salbutamol,cimetidine

Rubberprocessing Formaldehyde, ethylene diamine, phthalic anhydride

Plastics industry Toluene dissocyanate, hexamethyl dissocyanate,

dephenylmethyl isocyanate, phthalic anhydride,triethylene tetramines, trimellitic anhydride,hexamethyl tetramine, acrylates

*See http://www.bohrf.org.ukfor a comprehensive list of known sensitizing agents

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Diet. The role of diet, particularly breast-feeding, inrelation to the development of asthma has beenextensively studied and, in general, the data reveal thatinfants fed formulas of intact cow's milk or soy protein havea higher incidence of wheezing illnesses in early childhoodcompared with those fed breast milk88.

Some data also suggest that certain characteristics ofWestern diets, such as increased use of processed foodsand decreased antioxidant (in the formof fruitsand vegetables),increased n-6 polyunsaturated fatty acid (found in margarineand vegetable oil), and decreased n-3 polyunsaturatedfatty acid (found in oily fish) intakes have contributed tothe recent increases in asthma and atopic disease89.

MECHANISMS OF ASTHMA

Asthma is an inflammatory disorder of the airways, which

involves several inflammatory cells and multiple mediatorsthat result in characteristic pathophysiological changes21,90.In ways that are still not well understood, this pattern ofinflammation is strongly associated with airway hyper-responsiveness and asthma symptoms.

Airway Inflammation In Asthma

The clinical spectrum of asthma is highly variable, anddifferent cellular patterns have been observed, but thepresence of airway inflammation remains a consistentfeature. The airway inflammation in asthma is persistenteven though symptoms are episodic, and the relationshipbetween the severity of asthma and the intensity ofinflammation is not clearly established91,92. Theinflammation affects all airways including in most patientsthe upper respiratory tract and nose but its physiologicaleffects are most pronounced in medium-sized bronchi.The pattern of inflammation in the airways appears to besimilar in all clinical forms of asthma, whether allergic,non-allergic, or aspirin-induced, and at all ages.

Inflammatory cells. The characteristic pattern ofinflammation found in allergic diseases is seen in asthma,with activated mast cells, increased numbers of activated

eosinophils, and increased numbers of T cell receptorinvariant natural killer T cells and T helper 2 lymphocytes(Th2), which release mediators that contribute tosymptoms (Figure 1-4). Structural cells of the airwaysalso produce inflammatory mediators, and contribute to thepersistence of inflammation in various ways (Figure 1-5).

Inflammatory mediators. Over 100 different mediators arenow recognized to be involved in asthma and mediate thecomplex inflammatory response in the airways103 (Figure 1-6).


Figure 1-4: Inflammatory Cells in Asthmatic Airways

Mast cells: Activated mucosal mast cells release

bronchoconstrictor mediators (histamine, cysteinyl leukotrienes,

prostaglandin D2)93. These cells are activated by allergens

through high-affinity IgE receptors, as well as by osmotic stimuli

(accounting for exercise-induced bronchoconstriction). Increased

mast cell numbers in airway smoot

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